Version May 2024
INTRODUCTION — The SAPHO syndrome was given its acronymic name based upon the presence of synovitis, acne, pustulosis, hyperostosis, and osteitis in the patients described in early reports. It is a rare inflammatory disorder of bone, joints, and skin, which was first described as a syndrome in 1987 [1,2]. Many different names have been used for this syndrome, including sternocostoclavicular hyperostosis, acne-associated spondyloarthropathy, and pustulotic arthro-osteitis [3-5].
The relation of SAPHO syndrome to a similar condition, chronic recurrent multifocal osteomyelitis (CRMO), a form of chronic nonbacterial osteomyelitis (CNO) that is more common in children, remains uncertain [3,6,7]. (See "Chronic nonbacterial osteomyelitis (CNO)/chronic recurrent multifocal osteomyelitis (CRMO)".)
The clinical manifestations, diagnosis, and treatment of the SAPHO syndrome will be reviewed here. Other causes of musculoskeletal chest wall pain, including other autoinflammatory bone diseases (eg, CNO, Majeed syndrome, and deficiency of the interleukin [IL] 1 receptor antagonist), and other conditions causing a neutrophilic dermatosis are discussed separately:
●(See "Major causes of musculoskeletal chest pain in adults".)
●(See "Clinical evaluation of musculoskeletal chest pain".)
●(See "Management of isolated musculoskeletal chest pain".)
●(See "Neutrophilic dermatoses".)
PATHOGENESIS — The pathogenesis of SAPHO syndrome is not well understood; it is sometimes described as an autoinflammatory disorder, and a number of genetic and environmental (eg, infectious) factors and immune dysregulation have been proposed to contribute to disease susceptibility and development. These factors include:
●Genetic factors – The genetic bases of SAPHO syndrome remain largely unknown. Human leukocyte antigen (HLA) associations have been suggested in some studies, but none has been consistently observed, including HLA-A26, HLA-B27, HLA-B39, and HLA-B61 [4,8,9]. Several genes located on chromosomes 1 and 18 have been implicated in conditions similar to SAPHO syndrome, including LPIN2, PSTPIP2, and NOD2, but have not been found to be directly pathogenic in SAPHO syndrome itself [10,11]. A transcriptome analysis of patients with SAPHO syndrome indicates an overactive neutrophil recruitment profile [12].
●Infectious – Several bacterial pathogens have been implicated in case reports in which organisms have been isolated from bony lesions in patients with SAPHO. The bacteria found have included Cutibacterium (formerly termed Propionibacterium) acnes, the most commonly reported organism, as well as Staphylococcus aureus, Haemophilus parainfluenzae, Actinomyces, and others [13-15]. The most intriguing association may be with C. acnes, which may link together some of the cystic acneiform skin lesions with reports of bone culture findings. At least one study of 21 patients with SAPHO syndrome demonstrated C. acnes-positive bone cultures in two-thirds (14 of 21) of the patients [16]. However, a number of other studies have failed to confirm these observations [17].
●Immune dysregulation – It has been suggested that SAPHO syndrome represents a more autoinflammatory than autoimmune disorder, with findings including impaired p53 formation, increased interleukin (IL) 10 production, and decreased capacity to mount reactive oxygen species responses [11,18]. The inflammatory response observed in SAPHO includes a number of proinflammatory cytokines including IL-1, IL-8, IL-18, and tumor necrosis factor (TNF)-alpha [14]. Other autoinflammatory disorders of bone with similar features to SAPHO are also associated with increased IL-1 production [19]. Involvement of the T helper 17 (Th17) pathway has been implicated as well [20].
A hypothesis to link genetic factors, dysregulation of IL-1, and C. acnes infection in SAPHO has been postulated. This theory suggests that an autoinflammatory response might be triggered by a combination of FoxO1 deficiency or repression in skin and bone, defective autophagy, and infection with C. acnes [19].
SAPHO is thought by some experts to exist on a spectrum with the spondyloarthritides, other autoinflammatory disorders, and pustular dermatoses, given the presence of clinically overlapping rheumatologic features shared with conditions such as spondyloarthritis and chronic recurrent multifocal osteomyelitis (CRMO) and dermatologic features shared with the neutrophilic disorders of the skin [21].
EPIDEMIOLOGY — SAPHO syndrome is a rare disease, with limited data available regarding its prevalence, which has been estimated as 1 in 10,000 in White populations [22-24]. Many reports are from Europe (eg, France, Germany, Spain, and the Netherlands), but African American, Latin American, Japanese, Chinese, Australian, and other patients are reported, suggesting a worldwide distribution [4,7,25,26].
Individuals between the ages of 30 and 50 seem most frequently affected, but children and young adults have also been reported, as have older adults, with one report of a woman diagnosed at 80 years of age [8]. There is an apparent female predominance, particularly among patients less than 30 years of age at onset [23].
CLINICAL MANIFESTATIONS — Bone and joint (often termed "osteoarticular") manifestations of SAPHO syndrome are the hallmark of the disorder and occur regardless of the presence of active dermatologic findings; however, more than 60 percent of patients diagnosed with SAPHO develop an associated cutaneous manifestation, and additional features may also be present [23,24]. (See 'Cutaneous manifestations' below and 'Osteoarticular manifestations' below and 'Other manifestations' below.)
Osteoarticular manifestations
Clinical features — As its name implies, the SAPHO syndrome is characterized by a number of bone and joint findings that may present with symptoms of pain, swelling, and tenderness in involved areas. These features may be chronic or episodic and relapsing and focal or multifocal. The bone and joint features in individual patients include one or more of the following [27]:
●Synovitis, which is most often a nonerosive inflammatory arthritis, although periarticular osteopenia, joint space narrowing, and bony erosive changes associated with the synovitis and/or osteitis may occur.
●Osteitis, with pain, tenderness, and sometimes swelling of the bone due to focal inflammation of the cortex, the medullary cavity, or both.
●Hyperostosis, with bony overgrowth that is typically evident later in the disease course due to endosteal and/or periosteal proliferation. Sclerotic changes in the bone can result from trabecular and cortical thickening with narrowing of the medullary canal; concurrent osteolytic lesions may coexist when osteitis and hyperostosis are both present.
●Changes consistent with axial spondyloarthritis, affecting the sacroiliac joints and spine, and enthesitis (ie, inflammation and resultant pathologic change at the site of tendinous and ligamentous insertion into bone). Diffuse idiopathic skeletal hyperostosis (DISH)-like nonmarginal enthesophytes may occur.
Bone and joint involvement may affect a variety of regions, especially the anterior chest wall; other parts of the axial skeleton, including the sacroiliac joint and spine; and medium to large lower-extremity joints:
●Anterior chest wall involvement is seen in 65 to 90 percent of patients and considered highly characteristic of SAPHO syndrome; areas typically affected include the sternocostal and sternoclavicular joints as well as the costoclavicular ligament [28-31]. Soft tissue surrounding these areas may develop erythema and swelling. The affected areas may be tender on examination.
●Mandibular involvement has been reported, particularly among young women [32].
●The sacroiliac joint (more often), as well as the spine, are affected next most often after the chest wall (32 to 52 percent of patients) [29,30]. The sacroiliac involvement is often unilateral, and due primarily to osteitis, although synovitis may occur secondarily.
●Peripheral joint involvement is reported in less than 30 percent of patients. Hip, knee, and ankle joints are more commonly involved than upper-extremity joints. Soft tissue swelling can be marked and lead to compression of surrounding structures [30]. Mandibular involvement, particularly in the form of diffuse sclerosing sterile osteomyelitis, has also been reported [33-39]. (See "Chronic nonbacterial osteomyelitis (CNO)/chronic recurrent multifocal osteomyelitis (CRMO)", section on 'Clinical manifestations'.)
Musculoskeletal imaging features
Plain radiography — Radiographic changes may include: hyperostotic changes (thickening of periosteum, cortex, and endosteum), sclerotic lesions, osteolysis, periosteal reaction, and osteoproliferation involving entheses (with the formation of enthesophytes [osteophytes]) [29,30].
Plain radiographs remain normal for many months after disease onset, but changes develop in most patients over time. In one study, involving 19 patients with a mean disease duration of 12.3 years, radiographs were normal during the first three months after disease onset in 80 percent of patients, but radiographic changes developed in all patients by the end of the follow-up period [40]. In the bone, osteitis generally precedes sclerotic lesions (image 1) [30].
Axial involvement, including axial spondyloarthritis-related changes, osteitis, and ankylosis, is seen in both children and adults. Axial lesions include vertebral body corner lesions, nonspecific spondylodiscitis, osteodestructive lesions, osteosclerotic lesions, paravertebral ossification, and sacroiliitis [29,30].
Osteolytic lesions in vertebral bodies may be present and lead to variable collapse. The "corner lesion" seen in some patients is a focal cortical erosion at one of the vertebral body corners. Paravertebral ossification occurs most commonly as nonmarginal and asymmetric syndesmophyte formation, although marginal syndesmophytes may be seen. Sacroiliitis in SAPHO is usually unilateral with sclerosis and hyperostosis present on the iliac side of the joint, unlike typical spondyloarthritis [30].
Other imaging techniques — Additional imaging techniques beyond plain radiography can be very useful in identifying the extent of disease, the presence of osteitis and other characteristic findings, and in the diagnosis and differential diagnosis of SAPHO syndrome (image 2 and image 3 and image 4 and image 1). (See 'Approach to diagnosis' below and 'Patient evaluation' below and 'Differential diagnosis' below.)
●Computed tomography – Multidetector computed tomography (MDCT) can demonstrate the various osteoarticular manifestations and extent of disease burden (image 2 and image 3 and image 4) [30].
●Bone scan – Radionuclide bone scanning may demonstrate increased uptake at multiple sites of involvement. A so-called "bull's head" (or "lobster claw sign") change on bone scan imaging (image 2) is characteristic of SAPHO syndrome with sternoclavicular involvement. In the author's experience, bone scan has been most helpful for quickly surveying the entire skeleton for "typical" locations of involvement as an adjunct to more targeted imaging modalities.
●Magnetic resonance imaging – Magnetic resonance imaging (MRI) detects osteitis (bone marrow edema) not seen on plain radiograph and, in addition, offers soft tissue data (image 1). Structural lesions, such as erosions and ankylosis, can also be seen on MRI (T1-sequence) (image 4 and image 3). Whole-spine MRI techniques have demonstrated some distinct patterns of involvement between SAPHO syndrome patients and other spondyloarthritis (eg, sacroiliac involvement of only 7 versus 100 percent in the spondyloarthritis cohort evaluated) and may represent a particularly useful MRI study [41]. MRI has been suggested as a favored diagnostic modality [42].
●Positron emission tomography – Fluorodeoxyglucose positron emission tomography (FDG-PET)/CT can differentiate active from inactive lesions in SAPHO syndrome [43-47].
●Ultrasound – Synovitis with power doppler signals have been detected in sternoclavicular joints and peripheral joints of patients with SAPHO syndrome compared with controls and may represent a reasonable point-of-service, in-office evaluation opportunity [48].
Cutaneous manifestations — Skin findings in patients with SAPHO syndrome include a variety of acneiform and neutrophilic dermatoses (see "Neutrophilic dermatoses" and "Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris"). The time interval between the occurrence of initial skin and arthritis/osteitis symptoms is less than two years in approximately 70 percent of patients [49]. Exacerbation of osteoarticular and dermatologic manifestations are more often unrelated to each other than occurring together [50].
Palmoplantar pustulosis was reported as the most common manifestation in several series, affecting up to 60 percent of patients who develop skin manifestations (picture 1A-C) [7,8]. Moderate to severe forms of nodulocystic acne, involving the face, chest, and back, and often with residual scarring, are also typical, occurring in 25 percent of patients, particularly males (picture 2A-B). In addition to acne, other features of follicular occlusion syndromes may be present, including hidradenitis suppurativa [51,52]. (See "Neutrophilic dermatoses" and "Palmoplantar pustulosis: Epidemiology, clinical features, and diagnosis" and "Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris" and "Hidradenitis suppurativa: Pathogenesis, clinical features, and diagnosis".)
Other neutrophilic dermatoses, such as subcorneal pustular dermatosis (also known as Sneddon-Wilkinson disease), Sweet syndrome, and pyoderma gangrenosum, are less frequently reported as part of SAPHO [7,53]. Plaque psoriasis has also been reported [8,53]. (See "Neutrophilic dermatoses" and "Subcorneal pustular dermatosis" and "Sweet syndrome (acute febrile neutrophilic dermatosis): Pathogenesis, clinical manifestations, and diagnosis" and "Pyoderma gangrenosum: Pathogenesis, clinical features, and diagnosis".)
Other manifestations — Other manifestations and associated conditions include:
●Systemic (constitutional) features may include fatigue and fever.
●Inflammatory bowel disease (IBD) has been reported in up to 10 percent of patients with SAPHO syndrome in some series, with Crohn disease reported more often than ulcerative colitis [54-58]. The frequency remains uncertain given the associations with IBD of both neutrophilic dermatoses and inflammatory arthritis and spondyloarthritis in a pattern distinct from SAPHO. (See 'Differential diagnosis' below.)
●Other less frequent manifestations, for which there are one or multiple case reports:
•Venous thrombosis, most often affecting the subclavian vein [59-65]
•Hypertrophic pachymeningitis [66]
•Uveitis [52]
•Sciatica (probably from soft tissue involvement and encroachment on spinal nerves) [67]
•AA amyloidosis with related renal involvement [68-70]
•Pleural abnormalities including both parenchymal and pleural changes [71,72]
Laboratory findings — Nonspecific inflammatory changes may be seen, including elevations in the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), elevated complement levels, mild leukocytosis, and thrombocytosis, but are not universal. In one series, an elevated ESR was present in 30 percent of patients and CRP elevation in 53 percent of patients tested [73]. Mild anemia may be present. One study suggested increased levels of immunoglobulin A (IgA) in a cohort of patients with SAPHO syndrome with otherwise normal immunoglobulin levels [14]. The frequency of human leukocyte antigen (HLA)-B27 is not elevated [74].
DIAGNOSIS — The diagnosis of SAPHO syndrome can be challenging, given the wide variety of clinical features that may occur in these patients. In general, SAPHO syndrome should be suspected in patients with bone and joint symptoms consistent with inflammatory arthritis and/or osteitis, especially when it involves the anterior chest wall, sacroiliac joints, or spine, and particularly when occurring in association with a neutrophilic dermatosis or acneiform eruption.
The diagnosis of SAPHO syndrome remains largely a clinical diagnosis that is based upon the presence of a combination of features; it is also a diagnosis of exclusion that requires an absence of evidence to support an infectious, malignant, or other etiology. Classic rheumatic diseases, such as rheumatoid arthritis, axial spondyloarthritis, or psoriatic arthritis should also be excluded.
Other presentations may occur but are less common. In patients without skin disease at presentation, a past history of one of the typically associated skin disorders may be present, although some patients only develop skin manifestations subsequently, and they are occasionally absent even in follow-up.
Approach to diagnosis — Several sets of diagnostic approaches have been proposed that may serve as frameworks for making the diagnosis, but none of these have been validated for research or clinical use, and, like many criteria for a phenotypically heterogeneous and uncommon disorder, fall short in many individual cases of probable SAPHO (table 1A-C) [1,4,5]. In general, each of these proposed schema involves a form of bone and/or joint involvement typical of SAPHO that is usually present together with a form of skin disease typical of the syndrome or a past history of such skin manifestations. The published approaches typically require the exclusion of infectious, neoplastic, and other causes of the presenting features. Our approach is generally based upon these related sets of criteria, recognizing their individual limitations.
Thus, the diagnosis of SAPHO is likely, in our view, in patients with any one of the following characteristic presentations, and in whom infectious osteitis/osteomyelitis, malignancy, noninflammatory condensing lesions of bone, and other rheumatic and autoinflammatory disorders of bone and joints have been excluded:
●Osteoarticular disease associated with palmoplantar pustulosis – Bone and joint manifestations most often may include inflammatory synovitis or pseudoseptic arthritis; hyperostosis with or without osteitis involving the anterior chest wall or another site; or sacroiliitis, spondylitis, and/or spondylodiscitis.
●Osteoarticular disease associated with severe acne (eg, nodulocystic acne) or with hidradenitis suppurativa – Bone and joint manifestations most often may include inflammatory synovitis, or anterior chest wall hyperostosis or osteitis; hyperostosis or osteitis at another site; or sacroiliitis, spondylitis, and/or spondylodiscitis.
●Isolated sterile hyperostosis/osteitis – Bone and joint manifestations most often include sternocostoclavicular hyperostosis or other anterior chest wall hyperostosis or sterile osteitis, but sometimes they include limb or spine hyperostosis. Skin disease may or may not be present in patients with these osteoarticular features.
Some patients will not have one of the characteristic combinations of features described above, but the combination of findings present may be best described as the SAPHO syndrome rather than another rheumatologic or autoinflammatory disorder. Other presentations, as examples, may include:
●Characteristic osteoarticular findings of SAPHO (eg, chest wall osteitis or joint inflammation) in association with inflammatory bowel disease (IBD).
●Chronic recurrent multifocal osteomyelitis (CRMO), which is most often described in children, with axial or appendicular joint involvement, but with or without skin disease. Bone cultures are typically negative.
●Anterior chest wall osteitis/hyperostosis with psoriasis vulgaris.
Patient evaluation — In patients suspected of SAPHO syndrome, we perform a history and physical examination, as well as radiologic and laboratory assessment:
●History – Patients should undergo a thorough medical history, with particular attention to features that suggest inflammatory arthritis (eg, morning stiffness >30 minutes, joint swelling/pain, improvement with activity, axial involvement with pain waking from sleep, back pain and stiffness that improve with activity) and/or focal bone pain suggestive of osteitis. A history of skin disease should be sought, especially in patients without typical skin manifestations on examination.
Patients should be questioned regarding any history of inflammatory eye disease (ie, scleritis, uveitis) or gastrointestinal symptoms suggestive of IBD. Such findings may occur with SAPHO or independently of SAPHO. (See 'Differential diagnosis' below.)
A family history of spondyloarthritis, IBD, psoriasis, rheumatoid arthritis, or another autoimmune/autoinflammatory disease, which might indicate increased risk for one of these alternative diagnoses, should be sought. (See 'Differential diagnosis' below.)
●Physical examination – Patients should undergo a thorough examination of the bones and joints, with particular attention to tenderness to palpation over key sites such as the sternoclavicular, sternomanubrial, and costochondral sites. Examination of the sacroiliac joints and range of the motion of the cervical and lumbar spine is warranted in patients with symptoms of axial disease, but these findings will not help differentiate SAPHO from other diseases affecting the spine.
In addition, patients should undergo a thorough skin examination for signs of cutaneous findings associated with SAPHO. Examples include pustular eruptions and inflammatory nodules or plaques. (See 'Cutaneous manifestations' above.)
●Laboratory evaluation – There are no pathognomonic laboratory findings of SAPHO. However, we obtain the following tests during the initial evaluation to identify active inflammation, aid with excluding other disorders (eg, infection, rheumatoid arthritis), and for baseline studies before initiating drug therapies:
•Complete blood count and hepatic and renal chemistries
•Markers of inflammation, including the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)
•Rheumatoid factor and anticyclic citrullinated peptide antibodies, which are often positive in patients with rheumatoid arthritis, and may be helpful if there is diagnostic uncertainty, depending upon the clinical findings
•Human leukocyte antigen (HLA)-B27 testing, which would be positive more often in patients with spondyloarthritis and may be helpful if there is diagnostic uncertainty, depending upon the clinical findings
●Imaging evaluation – We initially obtain plain radiographs of affected areas, followed by a bone scan (whole-body scintigraphy) if radiographs are unrevealing or the diagnosis remains uncertain, as this may identify asymptomatic regions and multiple sites of disease [19]. Magnetic resonance imaging (MRI) of affected areas should be used for the detection of osteitis and better characterization of bone and soft tissue involvement. (See 'Musculoskeletal imaging features' above.)
We also obtain plain radiographs of the pelvis to evaluate the sacroiliac joints in patients with symptoms of inflammatory back pain. In patients in whom those studies are normal or findings are uncertain, we obtain MRI studies of the sacroiliac joints for further evaluation. This approach is similar to that taken in patients being evaluated for a possible spondyloarthropathy. (See "Diagnosis and differential diagnosis of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults", section on 'History' and "Diagnosis and differential diagnosis of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults", section on 'Imaging studies'.)
We generally only use whole-body MRI if better delineation is still required or the diagnosis continues to remain uncertain. However, MRI may be the modality of choice for young patients to avoid radiation exposure and as a sensitive method of detecting early lesions [41].
Fluorodeoxyglucose positron emission tomography (FDG-PET)/CT offers the advantage of differentiating active versus inactive lesions in SAPHO syndrome but has more limited availability than the other imaging modalities [43-46].
●Microbiology and histology – In patients in whom the radiologic evaluation raises concern for possible infection (osteomyelitis), tissue sampling in the form of needle aspiration or bone biopsy may be required for culture to help distinguish between osteomyelitis and the noninfectious/sterile osteitis typical of SAPHO. (See "Nonvertebral osteomyelitis in adults: Clinical manifestations and diagnosis".)
As examples, patients with a single bone lesion, lesions not responding to antiinflammatory therapies, or in the setting of other comorbidities that may predispose to or raise suspicion of osteomyelitis (eg, endocarditis, intravenous drug abuse history, or persistent high fevers) may require a bone biopsy and culture, depending upon the clinical findings present. A biopsy may also be required if malignancy is suspected. (See 'Differential diagnosis' below.)
Although the physical examination is usually sufficient for the diagnosis of some skin manifestations of SAPHO (eg, palmoplantar pustulosis, acne), additional testing (eg, biopsy or tissue culture) can be necessary for confirming the diagnosis of other skin diseases (eg, pyoderma gangrenosum, Sweet syndrome). (See "Pyoderma gangrenosum: Pathogenesis, clinical features, and diagnosis", section on 'Diagnosis' and "Sweet syndrome (acute febrile neutrophilic dermatosis): Pathogenesis, clinical manifestations, and diagnosis", section on 'Diagnosis'.)
DIFFERENTIAL DIAGNOSIS — Other inflammatory, infectious, and neoplastic etiologies should be considered when evaluating a patient for SAPHO syndrome.
●Osteoarticular disease – In regards to osteoarticular (bone and joint) manifestations, the primary disorders in the differential diagnosis are osteomyelitis and malignancy:
•Osteomyelitis – Early SAPHO may be difficult to distinguish from osteomyelitis, as they may both present with a local site of bone pain, tenderness, warmth, and swelling, with an associated fever. However, osteomyelitis is less likely to be multifocal, and culture of involved bone would distinguish sterile osteitis, as in SAPHO, from an infectious etiology. Bone scintigraphy may differentiate multiple-site inflammatory involvement from a more focal infection or malignancy at a single site. (See "Nonvertebral osteomyelitis in adults: Clinical manifestations and diagnosis".)
•Malignancy – Malignant disorders of bone such as osteosarcoma and metastatic cancer should be considered. Both osteosarcoma and SAPHO may present with localized bone pain and surrounding swelling and without systemic symptoms. However, unlike SAPHO, osteosarcoma typically occurs in a single bone lesion, often affects the long bones, and has distinct radiographic features. A biopsy can establish a definitive diagnosis. (See "Osteosarcoma: Epidemiology, pathology, clinical presentation, and diagnosis".)
Bone metastases can also present with bone pain. Common sites include the vertebral column, sacrum, pelvis, and femur. The diagnosis is made through identification of the primary site of cancer and supportive radiologic and/or bone biopsy findings. (See "Epidemiology, clinical presentation, and diagnosis of bone metastasis in adults".)
●Skin disease with osteoarticular manifestations – Patients with SAPHO syndrome should be distinguished from patients with osteoarticular manifestations occurring as a secondary feature of inflammatory skin disease. Bone or joint pain may occur in the context of isolated palmoplantar pustulosis, acne fulminans, psoriasis, pyoderma gangrenosum, and Sweet syndrome. The absence of a pattern of osteoarticular findings characteristic of SAPHO aids in distinguishing these conditions from SAPHO. (See "Palmoplantar pustulosis: Epidemiology, clinical features, and diagnosis" and "Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris", section on 'Acne fulminans' and "Psoriasis: Epidemiology, clinical manifestations, and diagnosis" and "Pyoderma gangrenosum: Pathogenesis, clinical features, and diagnosis" and "Sweet syndrome (acute febrile neutrophilic dermatosis): Pathogenesis, clinical manifestations, and diagnosis".)
●Systemic inflammatory/autoimmune disease with neutrophilic dermatoses – Patients with certain autoimmune diseases, such as rheumatoid arthritis and inflammatory bowel disease (IBD), which are characterized by or sometimes associated with inflammatory arthritis, respectively, have an increased risk for neutrophilic dermatoses. SAPHO syndrome is distinguished by the detection of a pattern of osteoarticular findings consistent with SAPHO. (See "Clinical manifestations of rheumatoid arthritis" and "Overview of the systemic and nonarticular manifestations of rheumatoid arthritis", section on 'Neutrophilic dermatoses' and "Clinical manifestations and diagnosis of arthritis associated with inflammatory bowel disease and other gastrointestinal diseases".)
TREATMENT — Treatment of osteoarticular and cutaneous manifestations of SAPHO syndrome is recommended for all patients not only for symptom relief but also because it is expected to minimize risk for joint injury and further complications. (See 'Prognosis' below.)
There is no single, optimal approach to the treatment of SAPHO syndrome, given both a paucity of high-quality treatment data and the wide variation in clinical presentations. No randomized trials have been performed and approaches to treatment are primarily guided by information from case reports, case series, or expert opinion and vary based upon the specific disease manifestations in individual patients.
Our approach — Our general approach to treating common presentations of SAPHO syndrome is reviewed here. Other approaches may be reasonable.
Patients with only osteoarticular manifestations — In patients with only osteoarticular manifestations (eg, synovitis, osteitis), we suggest initial therapy with a nonsteroidal antiinflammatory drug (NSAID) (see 'NSAIDs' below). An NSAID failure can normally be diagnosed after four weeks of treatment with at least two NSAIDs. Patients who require immediate relief from bone and joint pain and swelling may improve with a short course of oral glucocorticoid therapy (typically prednisone 10 to 20 mg per day), which should optimally be limited to two to four weeks of treatment. However, this is usually not necessary, and long-term glucocorticoid therapy should generally be avoided due to the risk of drug-related side effects. (See "Major adverse effects of systemic glucocorticoids".)
Patients who do not respond to these initial treatments may respond to other interventions. Our preferred second-line treatment options are methotrexate (MTX) and tumor necrosis factor (TNF) inhibitors (eg, etanercept, adalimumab, infliximab).
●In patients with peripheral arthritis without axial disease (ie, without chest wall osteitis or synovitis, sacroiliitis, spondylitis, or spondylodiscitis), we suggest MTX based upon extensive experience with this agent in inflammatory arthritis, reports of its efficacy in patients with SAPHO, the availability of an oral formulation, and the low cost of MTX compared with TNF inhibitors (see 'Methotrexate' below). In patients with peripheral arthritis who have an inadequate response to MTX after three months, we suggest treatment with a TNF inhibitor, which may be done either by switching agents or continuing the MTX and adding the TNF inhibitor.
In patients with severe enthesitis who have an inadequate response to NSAIDs, we prefer use of a TNF inhibitor. There is no convincing evidence in patients with axial spondyloarthritis or psoriatic arthritis that conventional disease-modifying antirheumatic drugs (DMARDs), including MTX, are effective for the treatment of enthesitis [75,76]. However, data from clinical trials involving patients with enthesitis and other musculoskeletal disease manifestations as a peripheral manifestation of spondyloarthritis or psoriatic arthritis have documented the efficacy of TNF inhibitors and other biologics in many such patients. (See "Treatment of peripheral spondyloarthritis", section on 'Enthesitis'.)
●In patients with axial disease (ie, sacroiliitis, spondylitis, spondylodiscitis) who do not respond to NSAIDs with adequate symptom relief, we suggest a TNF inhibitor rather than a conventional DMARD such as MTX (see 'TNF inhibitors' below). In spondyloarthritis and SAPHO, in our experience, MTX often does not sufficiently improve axial manifestations (see 'Methotrexate' below). We also prefer a TNF inhibitor in patients whose axial disease is primarily in the chest wall (eg, osteitis or synovitis affecting the sternocostal or sternoclavicular joints or the costoclavicular ligament), but some regulators or payors may require a trial of a conventional DMARD, such as MTX, prior to approving payment or coverage for a biologic agent. There are no data to indicate a preference for one TNF inhibitor over another in patients with osteoarticular manifestations alone, but in patients with severe psoriatic skin disease, uveitis, or selected other manifestations, we prefer one of the monoclonal antibodies rather than etanercept. (See 'Patients with both osteoarticular and other manifestations' below.)
Colchicine and sulfasalazine are generally well-tolerated alternative second-line therapies that may be sufficient for patients with mild arthritis who fail to respond adequately to NSAIDs or cannot tolerate NSAIDs [23]. In our experience, these agents often are not adequate for patients with more severe symptoms. (See 'Other agents' below.)
Because the disease course is typically chronic with relapsing and remitting symptoms, we continue therapy based upon the patient's symptoms. Once the patient is stable, in a state of remission or low disease activity, we very gradually reduce the number and strength of medications with close monitoring to resume prior treatment if there are disease flares. In the author's experience, TNF inhibitors may be required at higher doses such as those used for hidradenitis suppurativa or inflammatory bowel disease (IBD) in order to achieve disease control in patients with SAPHO syndrome. There are no data to support or refute benefit (eg, reduced bone and joint injury) from sustained long-term treatment in asymptomatic patients.
Patients with both osteoarticular and other manifestations — The approach to treatment of multisystem manifestations of SAPHO differs depending upon the specific features present. In some scenarios, such as SAPHO occurring with palmoplantar pustulosis or acne, the same agent or treatment regimen may result in improvement in both osteoarticular and non-osteoarticular manifestations. Our typical initial interventions for patients with SAPHO and these skin disorders include:
●SAPHO syndrome with palmoplantar pustulosis – In patients with extensive palmoplantar pustulosis and SAPHO, an oral retinoid is our preferred first-line treatment because retinoids are effective for palmoplantar pustulosis and may also impact osteoarticular manifestations. We typically use acitretin. MTX monotherapy and/or in combination with acitretin may be required for resistant disease. Some success with oral dapsone therapy has also been reported [77]. Intermittent use of potent topical steroids, hand-foot ultraviolet (UV) therapy, and other adjunctive therapies may be attempted. (See 'Oral retinoids' below and "Palmoplantar pustulosis: Treatment", section on 'First-line therapy'.)
●SAPHO syndrome with acne – In patients with SAPHO syndrome with moderate to severe acne, use of antibiotics with antiinflammatory properties may improve both skin and bone symptoms. We most often use oral tetracyclines as initial treatment, though other antibiotics may also be of benefit. In patients presenting with severe, scarring acne or palmoplantar pustulosis, oral isotretinoin is our preferred first-line therapy, as isotretinoin is an appropriate treatment for severe, scarring acne and may also improve osteoarticular manifestations. (See 'Antibiotics' below and 'Oral retinoids' below and "Acne vulgaris: Overview of management" and "Oral isotretinoin therapy for acne vulgaris".)
Patients with an inadequate response to a unified approach to therapy (eg, retinoids or antibiotics, without MTX or a TNF inhibitor) and patients who exhibit other combinations of features may require separate approaches for the individual components of the syndrome. When treatment options for bone/joint and other manifestations do not overlap, we suggest combining treatments used for the bone and joint manifestations (see 'Patients with only osteoarticular manifestations' above) with the standard therapeutic approach for the specific associated cutaneous or systemic manifestation (see appropriate topic reviews).
Resistant to usual therapies — In patients who do not respond to standard therapies for their skin and bone and joint manifestations, there are limited data to guide therapy. Depending upon the particular manifestations present and the severity of disease, the following treatments and several others, including local injection, may be useful in selected patients (see 'Other agents' below):
●Bisphosphonates
●Anti-interleukin (IL) 1 therapy
●Anti-IL-12/23 or anti-IL-17 therapies
●Janus kinase (JAK) inhibitors
Treatment options
NSAIDs — NSAIDS are the primary initial treatment for osteoarticular manifestations of SAPHO. There are no data that suggest greater or lesser benefit from any particular NSAID for the treatment of this condition. Common regimens for adults used by the author include naproxen (500 mg twice daily), ibuprofen (600 to 800 mg three times daily), and indomethacin (50 mg two to three times daily). Other agents may be favored in different geographic regions or by different experts (eg, in Europe, it would be more common to use diclofenac, celecoxib, or etoricoxib). Improvement in osteoarticular symptoms is often evident within seven to ten days, as with other inflammatory arthritides.
Use of NSAID therapy for osteoarticular manifestations of SAPHO is based upon clinical experience, published case series [50], and the benefit of these agents in multiple other inflammatory conditions. There are no randomized trials to document benefit in this disorder.
NSAID use is associated with risk for side effects such as gastrointestinal, renal, and cardiovascular effects. These drugs should be used with caution or avoided in patients at high risk of or with known peptic ulcer disease, renal insufficiency, or cardiovascular disease. The adverse effects of NSAIDs are reviewed in detail separately. (See "Nonselective NSAIDs: Overview of adverse effects" and "Overview of COX-2 selective NSAIDs", section on 'Toxicities and possible toxicities'.)
Antibiotics — Antibiotic therapy for SAPHO syndrome is primarily employed for patients with associated moderate to severe acne. Oral antibiotics are effective for acne and may also improve osteoarticular manifestations of SAPHO syndrome. The antiinflammatory effects of antibiotics are postulated to contribute to improvement.
As in isolated acne vulgaris, tetracyclines are typical first-line agents. Common regimens include doxycycline (100 mg twice daily) and minocycline (100 mg twice daily). Improvement in acne may be evident as early as the first few weeks of treatment. Osteoarticular symptoms may also improve.
We typically use the full dose for one to three months, depending upon the response, then reduce the dose to once daily in patients who have responded well. Patients who have not had an adequate response within three months require an alternative or additional therapy. We treat for an additional three months in such patients until attempting further dose reduction (eg, to doxycycline 40 mg extended release once daily) or discontinuation.
The benefit of tetracyclines in SAPHO syndrome is supported by limited data from small case series and our clinical experience [8,78].
Common side effects of tetracyclines include gastrointestinal distress and photosensitivity. In particular, minocycline has also been associated with vertigo and a lupus-like syndrome. Use of tetracyclines should be avoided in pregnant women and children under the age of nine due to the potential for discoloration of developing permanent teeth. (See "Acne vulgaris: Management of moderate to severe acne in adolescents and adults", section on 'Oral antibiotics'.)
Other antibiotics may also yield improvement in SAPHO syndrome associated with acne. An alternative agent is trimethoprim/sulfamethoxazole (160/800 mg orally twice daily in adults); other experts have described benefit from azithromycin and clindamycin [8,16,79,80].
Methotrexate — Peripheral arthritis in patients with SAPHO may respond to MTX. Typical doses used for adults are 15 to 25 mg once weekly taken orally, but these doses may be better absorbed given parenterally if needed. Improvement in osteoarticular symptoms can occur within several weeks to months in our experience. Once satisfactory improvement in symptoms is achieved, we attempt to gradually reduce the dose of medication while closely monitoring for recurrence (see 'Patients with only osteoarticular manifestations' above). We employ the same approach to dosing and use of MTX as is used and described separately in detail for the treatment of rheumatoid arthritis. (See "Initial treatment of rheumatoid arthritis in adults", section on 'Initial therapy with methotrexate' and "Use of methotrexate in the treatment of rheumatoid arthritis".)
MTX seems to be most appropriate for the treatment of SAPHO syndrome patients with peripheral arthritis and without axial disease both in our experience and based upon its lack of effectiveness for axial spondyloarthritis and psoriatic arthritis. The efficacy of MTX for the treatment of osteitis or enthesitis is uncertain. MTX also does not appear highly effective in treating the skin manifestations. However, there are small numbers of case reports of its successful use in some patients with SAPHO syndrome [8,51,81,82].
In spondyloarthritis and SAPHO, in our experience, MTX often does not sufficiently improve axial manifestations. (See "Treatment of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults" and "Treatment of psoriatic arthritis".)
Examples of adverse effects of MTX include stomatitis gastrointestinal distress, hematologic toxicity, hepatotoxicity, and pulmonary toxicity. Concomitant administration of folic acid is recommended and may reduce risk for some side effects. (See "Major side effects of low-dose methotrexate".)
TNF inhibitors — Treatment with a TNF inhibitor (eg, etanercept, adalimumab, infliximab) is used for SAPHO manifesting with peripheral arthritis, osteitis, or enthesitis that is not controlled adequately with MTX and is used for axial (including chest wall) manifestations in patients with an inadequate response to NSAIDs. Dosing regimens for these agents are similar to those used for psoriatic arthritis or spondyloarthritis. (See "Treatment of psoriatic arthritis" and "Treatment of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults".)
Use of TNF inhibitors is supported by case reports and series that describe effective use of TNF inhibitor therapy for SAPHO [83-90]. Treatment with these TNF inhibitors has generally been associated with improvement in bone pain and arthritis symptoms, sometimes within weeks of initiating therapy and often within approximately one to two months. In our experience, patients with SAPHO syndrome often require higher doses of TNF inhibitor therapy, approaching that of hidradenitis suppurativa or IBD dosing.
In cases of SAPHO with concurrent hidradenitis suppurativa, uveitis, IBD, or pyoderma gangrenosum lesions, we favor a monoclonal antibody-based TNF inhibitor therapy (eg, adalimumab or infliximab) instead of etanercept, as a variety of evidence suggests that etanercept is less effective for these conditions in isolation. (See "Uveitis: Treatment", section on 'Anti-tumor necrosis factor-alpha' and "Hidradenitis suppurativa: Management" and "Pyoderma gangrenosum: Treatment and prognosis".)
Examples of potential adverse effects of TNF inhibitors include injection-site reactions, infusion reactions, neutropenia, infection, demyelinating disease, and heart failure. The adverse effects are reviewed in detail separately. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects".)
Oral retinoids — Oral retinoid therapy (eg, acitretin, isotretinoin) is a preferred treatment choice in patients who would also benefit from retinoids for cutaneous manifestations (eg, palmoplantar pustulosis, acne); these agents have shown benefit in patients with SAPHO [79,81]. These agents are used in patients with SAPHO syndrome using the same protocols as in patients with acne, including with respect to total cumulative dose recommendations. Usual courses are six to nine months in duration. (See "Oral isotretinoin therapy for acne vulgaris".)
Oral retinoid therapy may be associated with side effects such as cheilitis, xerosis, hypertriglyceridemia, hair loss, bone changes (changes with chronic use suggestive of diffuse idiopathic skeletal hyperostosis [DISH]), and visual changes. Oral retinoids are contraindicated in pregnancy. In particular, women should avoid pregnancy for one month after completion of isotretinoin and for three years after completion of acitretin. (See "Oral isotretinoin therapy for acne vulgaris".)
Other agents — Other, less commonly used treatments have been described as beneficial in SAPHO syndrome in case reports or case series. An open-label study of pamidronate, a bisphosphonate, in 30 patients suggested improvement, including with spinal involvement [91], as have smaller case series with bisphosphonates, most often with pamidronate [8,81,92-102]. Other agents that have been reported to show benefit have included colchicine, sulfasalazine, systemic glucocorticoids, and other agents [4,7,8,25,27,78,84], anakinra [84,103], ustekinumab [104], secukinumab [104], tofacitinib [105-108], and apremilast [109,110]. A systematic review supports the use of several mechanisms listed above, including TNF inhibitors with a high response across bone, joint, and skin manifestations; IL-1 therapy is showing encouraging results in bone/joint but without improvement in skin manifestations, and more modest results from IL-17 and IL-12/23 inhibition [110]. Anti-IL-6 therapy has been tried in several patients but was deemed not effective [68,111].
It is postulated that anti-IL-12/23 or anti-IL-17 therapies (eg, ustekinumab, secukinumab, ixekizumab) may be beneficial based upon the limited case reports in patients with SAPHO syndrome [104], some evidence of involvement of the T helper 17 (Th17) pathway in the pathogenesis of the disease (see 'Pathogenesis' above) and the efficacy of these agents in psoriatic arthritis and spondyloarthritis (see "Treatment of psoriatic arthritis" and "Treatment of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults"). Further data are needed to determine the role of these agents in the treatment of SAPHO syndrome [112].
A few case reports have noted rapid improvement in SAPHO syndrome with the use of oral tofacitinib, a JAK inhibitor, in combination with MTX and a bisphosphonate in one subject [105,106].
The author has also used intraarticular glucocorticoid injections for isolated sternocostoclavicular involvement and in patients with otherwise well-controlled disease with a focal residual area of activity in the sternocostoclavicular joints. However, one case series using this technique in patients with SAPHO syndrome was unable to document benefit of such therapy in patients with sternoclavicular osteitis due to SAPHO syndrome [113]. Similarly, temporomandibular joint and focal mandibular joint involvement has been successfully treated with intralesional/intraarticular glucocorticoid injection in several of our patients.
PROGNOSIS — SAPHO syndrome is a chronic condition in the vast majority of cases and will follow a stable chronic or relapsing-remitting course. Although the course is variable, disabling complications are not common, although peripheral arthritis may be erosive, and bone and limb length discrepancies may occur.
In one study, after an average follow-up of 12 years, 53 percent of patients had evidence of new areas of osteoarticular involvement on imaging, suggesting that over the long term there was relatively little progression after a period of disease activity earlier in the course [40]. Female sex, anterior chest wall involvement, peripheral arthritis, skin involvement, and high inflammatory markers at initial presentation were associated with a more chronic disease course [24].
SUMMARY AND RECOMMENDATIONS
●Synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome is a rare chronic inflammatory disorder of bone, joint, and skin characterized by synovitis, osteitis, hyperostosis, and enthesitis, typically with pain, swelling, and tenderness in affected areas. A variety of regions may be involved, especially the anterior chest wall; other parts of the axial skeleton, including the sacroiliac joint and spine; and medium to large lower-extremity joints. Radiographic changes may include hyperostotic changes, sclerotic lesions, osteolysis, periosteal reaction, and osteoproliferation involving entheses. (See 'Pathogenesis' above and 'Epidemiology' above and 'Clinical manifestations' above and 'Osteoarticular manifestations' above.)
●The skin manifestations include a spectrum of follicular occlusion and neutrophilic dermatoses including severe acne, hidradenitis suppurativa, palmoplantar pustulosis, and pyoderma gangrenosum. The time interval between the occurrence of initial skin and arthritis/osteitis symptoms is less than two years in approximately 70 percent of patients, but not all patients exhibit cutaneous manifestations. (See 'Cutaneous manifestations' above.)
●The diagnosis of SAPHO syndrome should be suspected in patients with bone and joint symptoms consistent with inflammatory arthritis and/or osteitis, especially when they involve the anterior chest wall, sacroiliac joints, or spine, and particularly when occurring in association with a neutrophilic dermatosis or acneiform eruption. It is a diagnosis of exclusion that requires an absence of evidence to support an infectious, malignant, or other etiology. One of several more typical patterns of disease may be seen (table 1A-C), and diagnostic criteria have been proposed. (See 'Diagnosis' above and 'Differential diagnosis' above.)
●In patients with only osteoarticular manifestations, we suggest initial therapy with a nonsteroidal antiinflammatory drug (NSAID) rather than analgesics alone or more potent immunosuppressive agents. Treatment is with antiinflammatory doses (eg, naproxen 500 mg twice daily, ibuprofen 800 mg three times daily). (See 'Patients with only osteoarticular manifestations' above and 'NSAIDs' above.)
●In patients who require immediate relief from bone and joint pain and swelling, we suggest a short course of oral glucocorticoid therapy (typically prednisone 10 to 20 mg per day), which should optimally be limited to two to four weeks of treatment. We avoid long-term management with glucocorticoids. (See 'Patients with only osteoarticular manifestations' above.)
●In patients with only bone and joint disease with an inadequate response after four weeks of treatment with at least two different NSAIDs or short-term glucocorticoids, treatment depends upon the pattern of joint involvement:
•In patients with peripheral arthritis without axial disease (ie, without chest wall osteitis or synovitis, sacroiliitis, spondylitis, or spondylodiscitis), we suggest methotrexate (MTX; 15 to 25 mg once weekly). (See 'Patients with only osteoarticular manifestations' above and 'Methotrexate' above.)
•In patients with peripheral arthritis who have an inadequate response to MTX after three months, we use a tumor necrosis factor (TNF) inhibitor, which may be done either by switching agents or continuing the MTX and adding the TNF inhibitor. Any of the TNF inhibitors may be used in doses standard for inflammatory arthritis or spondyloarthritis. (See 'Patients with only osteoarticular manifestations' above and 'TNF inhibitors' above.)
•In patients with severe enthesitis and those with axial disease, including disease of the chest wall, who have an inadequate response to NSAIDs, we prefer use of one of the TNF inhibitors, rather than MTX or another conventional disease-modifying antirheumatic drug (DMARD). In patients with severe psoriatic skin disease, uveitis, or selected other manifestations, we prefer one of the monoclonal antibodies rather than etanercept. In our experience, higher doses than are used for spondyloarthritis may be required in more resistant disease, such as those for hidradenitis suppurativa or inflammatory bowel disease (IBD). (See 'Patients with only osteoarticular manifestations' above and 'TNF inhibitors' above.)
•Approaches to resistant disease beyond use of NSAIDs, MTX, and TNF inhibitors may include trials of bisphosphonate therapy, interleukin (IL) 17 inhibition, IL-1 inhibition, IL-12/23 inhibition, and smaller reports suggested Janus kinase (JAK) inhibition, depending on the resistant component of disease (ie, axial, bone, joint, skin). (See 'Resistant to usual therapies' above and 'Other agents' above.)
●The approach to treatment of multi-system manifestations of SAPHO differs depending upon the specific features present:
•In patients with extensive palmoplantar pustulosis and SAPHO, an oral retinoid (eg, acitretin) is our preferred first-line treatment because retinoids are effective for palmoplantar pustulosis and may also improve osteoarticular manifestations. Combination therapy with MTX may also be considered. (See 'Patients with both osteoarticular and other manifestations' above and 'Oral retinoids' above.)
•In patients with moderate to severe acne, we use oral tetracyclines as initial treatment, though other antibiotics may also be of benefit. In patients presenting with severe, scarring acne or palmoplantar pustulosis, oral isotretinoin is our preferred first-line therapy; it may also improve osteoarticular manifestations. (See 'Patients with both osteoarticular and other manifestations' above and 'Oral retinoids' above and 'Antibiotics' above.)
•Patients with an inadequate response to a unified approach to therapy and patients who exhibit other combinations of features may require separate approaches for the individual components of the syndrome. When treatment options for bone/joint and other manifestations do not overlap, we combine treatments used for the bone and joint manifestations with the standard therapeutic approach for the specific associated cutaneous or systemic manifestation. (See 'Patients with only osteoarticular manifestations' above and 'Patients with both osteoarticular and other manifestations' above.)
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